Hormone dependence in experimental breast cancer is a complex phenomenon involving the concerted action of a number of hormones. In many instances, modifications occur in the chain of biochemical events controlling tumor growth and result in a loss or alteration of hormonal control. Although a loss of certain receptors accounts for a loss of hormone responsiveness in some tumors, it is becoming evident that alterations in endocrine regulation of hormone receptors may be a critical determinant of hormone dependence. We propose to study hormonal regulation of receptors for estrogen, progesterone and prolactin in normal mouse mammary tissue in DDD mice and in a transplantable pregnancy-dependent mouse mammary tumor (TPDMT-4) which is clearly dependent on all these hormones for growth. Receptor assays will be developed to determine the total number of estrogen and progesterone receptors (free plus occupied) in both nuclear and cytoplasmic compartments and the total number of cell-surface receptors for prolactin. The dose-related effects of insulin, estrogen, progesterone and prolactin, singly and in combination, will be examined to determine if there are fundamental - possibly oncogenically relevant - differences in the level of receptors and/or receptor regulation in normal and neoplastic mammary tissue. These studies should define the relative usefulness of prolactin, estrogen and progesterone receptors as predictive markers of hormone dependence and provide insight into the complex hormonal interrelationships governing hormone-dependent tumors. Definition of key steps in the hormonal stimulatory pathway may ultimately lead to more rational approaches to endocrine therapy for individual breast cancer patients.